Trial Outcomes & Findings for Safety and Efficacy Study of Ipilimumab 3 mg/kg Versus Ipilimumab 10 mg/kg in Subjects With Metastatic Castration Resistant Prostate Cancer Who Are Chemotherapy Naive (NCT NCT02279862)

Last Updated: 2019-08-28

Results Overview

rPFS was defined as the time from the date of randomization until the date of disease progression based on radiographic evidence and/or death from any cause, whichever occurs first. Radiographic disease progression is defined as: Confirmed bone disease progression according to criteria adapted from the Prostate Cancer Clinical Trials Working Group 2 (PCWG2), OR Non-bone disease progression according to the modified Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. After termination of the study, collection of tumor assessments and other data to support the efficacy analyses was no longer required in patients who discontinued study treatment. As a result, the presented efficacy results are based on limited data. The number of participants with reported radiographic progression is shown.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

82 participants

Primary outcome timeframe

From date of randomization until disease progression or death (assessed up to December 2016, approximately 24 months)

Results posted on

2019-08-28

Participant Flow

82 participants were enrolled; 53 were randomized; 51 were treated with study drug. 29 were not randomized due to screening failures. 2 were randomized and not treated due to administrative reason by sponsor and "other" reason

Participant milestones

Participant milestones
Measure	Ipilimumab 3 mg/kg Ipilimumab at 3 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.	Ipilimumab 10 mg/kg Ipilimumab at 10 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.
Overall Study STARTED	26	27
Overall Study Treated	25	26
Overall Study COMPLETED	0	2
Overall Study NOT COMPLETED	26	25

Reasons for withdrawal

Reasons for withdrawal
Measure	Ipilimumab 3 mg/kg Ipilimumab at 3 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.	Ipilimumab 10 mg/kg Ipilimumab at 10 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.
Overall Study Study drug toxicity	3	6
Overall Study No longer meets criteria	0	1
Overall Study Administrative reason by sponsor	0	1
Overall Study Disease progression	5	2
Overall Study Study closed by sponsor	16	13
Overall Study Other	1	2
Overall Study Withdrawal by Subject	1	0

Baseline Characteristics

Safety and Efficacy Study of Ipilimumab 3 mg/kg Versus Ipilimumab 10 mg/kg in Subjects With Metastatic Castration Resistant Prostate Cancer Who Are Chemotherapy Naive

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ipilimumab 3 mg/kg n=25 Participants Ipilimumab at 3 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.	Ipilimumab 10 mg/kg n=26 Participants Ipilimumab at 10 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.	Total n=51 Participants Total of all reporting groups
Age, Continuous	66.00 years FULL_RANGE 8.23 • n=93 Participants	66.50 years FULL_RANGE 9.98 • n=4 Participants	66.00 years FULL_RANGE 9.08 • n=27 Participants
Sex: Female, Male Female	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Sex: Female, Male Male	25 Participants n=93 Participants	26 Participants n=4 Participants	51 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants
Race (NIH/OMB) White	25 Participants n=93 Participants	24 Participants n=4 Participants	49 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants

PRIMARY outcome

Timeframe: From date of randomization until disease progression or death (assessed up to December 2016, approximately 24 months)

Population: All randomized participants

Outcome measures

Outcome measures
Measure	Ipilimumab 3 mg/kg n=26 Participants Ipilimumab at 3 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.	Ipilimumab 10 mg/kg n=27 Participants Ipilimumab at 10 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.
Radiographic Progression-free Survival (rPFS)	4 Participants	3 Participants

SECONDARY outcome

Timeframe: From first dose of ipilimumab to last dose plus 90 days

Population: All treated participants

The total number of participants with immune-related adverse events of any grade is reported for each arm.

Outcome measures

Outcome measures
Measure	Ipilimumab 3 mg/kg n=25 Participants Ipilimumab at 3 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.	Ipilimumab 10 mg/kg n=26 Participants Ipilimumab at 10 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.
Number of Participants Who Experienced Immune-related Adverse Events (irAEs)	13 Participants	18 Participants

SECONDARY outcome

Timeframe: From randomization to death from any cause (assessed up to December 2016, approximately 24 months)

Population: All randomized participants

OS was defined as the time from the date of randomization until the date of death. For those participants who have not died, OS was censored at the last date the participant was known to be alive. After termination of the study, collection of tumor assessments and other data to support the efficacy analyses was no longer required in patients who discontinued study treatment. As a result, the presented efficacy results are based on limited data. The total number of reported deaths is shown.

Outcome measures

Outcome measures
Measure	Ipilimumab 3 mg/kg n=26 Participants Ipilimumab at 3 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.	Ipilimumab 10 mg/kg n=27 Participants Ipilimumab at 10 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.
Overall Survival (OS)	4 Participants	6 Participants

SECONDARY outcome

Timeframe: From randomization to the earliest date of PSA progression or death, whichever comes earlier (assessed up to December 2016, approximately 24 months)

Population: All randomized participants

Prostate specific antigen progression-free survival (PSA PFS) was defined as the time from randomization to the earliest date of PSA progression or death, whichever occurs earlier. Participants who did not progress or die were censored at the last PSA assessment date. After termination of the study, collection of tumor assessments and other data to support the efficacy analyses was no longer required in patients who discontinued study treatment. As a result, the presented efficacy results are based on limited data. The number of participants with reported PSA progression is shown.

Outcome measures

Outcome measures
Measure	Ipilimumab 3 mg/kg n=26 Participants Ipilimumab at 3 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.	Ipilimumab 10 mg/kg n=27 Participants Ipilimumab at 10 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.
Prostate Specific Antigen Progression-free Survival (PSA PFS)	4 Participants	3 Participants

SECONDARY outcome

Timeframe: From randomization until pain progression (assessed up to December 2016, approximately 24 months)

Population: All randomized participants

Pain progression was defined as an increase in BPI-SF pain Item #3 score of \>= 2 point from baseline maintained over 2 consecutive periods. After termination of the study, collection of tumor assessments and other data to support the efficacy analyses was no longer required in patients who discontinued study treatment, and presented efficacy results are based on limited data. The number of participants with reported pain progression is shown.

Outcome measures

Outcome measures
Measure	Ipilimumab 3 mg/kg n=26 Participants Ipilimumab at 3 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.	Ipilimumab 10 mg/kg n=27 Participants Ipilimumab at 10 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.
Time to Pain Progression	0 Participants	1 Participants

SECONDARY outcome

Timeframe: From baseline to PSA response (assessed up to December 2016, approximately 48 months)

Population: All randomized participants

PSA response rate was defined as the proportion of participants with a 50% or greater decrease from baseline to the lowest post-baseline PSA result (confirmed 3 weeks later) for each randomized arm. After termination of the study, collection of tumor assessments and other data to support the efficacy analyses was no longer required in patients who discontinued study treatment. As a result, the presented efficacy results are based on limited data. The number of participants showing PSA response is shown.

Outcome measures

Outcome measures
Measure	Ipilimumab 3 mg/kg n=26 Participants Ipilimumab at 3 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.	Ipilimumab 10 mg/kg n=27 Participants Ipilimumab at 10 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.
Prostate Specific Antigen Response Rate	0 Participants	1 Participants

Adverse Events

10 MG/KG IPILIMUMAB

Serious events: 15 serious events

Other events: 22 other events

Deaths: 0 deaths

3 MG/KG IPILIMUMAB

Serious events: 6 serious events

Other events: 22 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	10 MG/KG IPILIMUMAB n=26 participants at risk Ipilimumab at 10 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.	3 MG/KG IPILIMUMAB n=25 participants at risk Ipilimumab at 3 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.
Cardiac disorders Myocardial infarction	3.8% 1/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Endocrine disorders Adrenal insufficiency	3.8% 1/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Endocrine disorders Hypophysitis	3.8% 1/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Gastrointestinal disorders Autoimmune colitis	0.00% 0/26 • From date of first dose to date of last dose of study therapy plus 90 days	4.0% 1/25 • From date of first dose to date of last dose of study therapy plus 90 days
Gastrointestinal disorders Colitis	15.4% 4/26 • From date of first dose to date of last dose of study therapy plus 90 days	12.0% 3/25 • From date of first dose to date of last dose of study therapy plus 90 days
Gastrointestinal disorders Diarrhoea	26.9% 7/26 • From date of first dose to date of last dose of study therapy plus 90 days	4.0% 1/25 • From date of first dose to date of last dose of study therapy plus 90 days
Gastrointestinal disorders Pancreatitis	3.8% 1/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
General disorders General physical health deterioration	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
General disorders Pyrexia	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Hepatobiliary disorders Hepatitis	3.8% 1/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Infections and infestations Bacterial diarrhoea	0.00% 0/26 • From date of first dose to date of last dose of study therapy plus 90 days	4.0% 1/25 • From date of first dose to date of last dose of study therapy plus 90 days
Infections and infestations Pneumonia	0.00% 0/26 • From date of first dose to date of last dose of study therapy plus 90 days	4.0% 1/25 • From date of first dose to date of last dose of study therapy plus 90 days
Infections and infestations Septic shock	3.8% 1/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Infections and infestations Urinary tract infection	0.00% 0/26 • From date of first dose to date of last dose of study therapy plus 90 days	4.0% 1/25 • From date of first dose to date of last dose of study therapy plus 90 days
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/26 • From date of first dose to date of last dose of study therapy plus 90 days	4.0% 1/25 • From date of first dose to date of last dose of study therapy plus 90 days
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/26 • From date of first dose to date of last dose of study therapy plus 90 days	4.0% 1/25 • From date of first dose to date of last dose of study therapy plus 90 days
Renal and urinary disorders Hydronephrosis	3.8% 1/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Renal and urinary disorders Renal failure	3.8% 1/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.8% 1/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Respiratory, thoracic and mediastinal disorders Pneumothorax	3.8% 1/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days

Measure	10 MG/KG IPILIMUMAB n=26 participants at risk Ipilimumab at 10 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.	3 MG/KG IPILIMUMAB n=25 participants at risk Ipilimumab at 3 mg/kg was administered by intravenous (IV) infusion over a time period of 60-100 minutes, based on body weight. Induction Phase dosing consisted of a single dose every 3 weeks (Q3W) for 4 doses. This was followed by Maintenance Phase dosing of a single dose every 12 weeks (Q12W). Treatment was for a maximum treatment period of 3 years from the first induction dose of blinded study therapy, or until subject met treatment stopping criteria.
Blood and lymphatic system disorders Anaemia	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	12.0% 3/25 • From date of first dose to date of last dose of study therapy plus 90 days
Gastrointestinal disorders Colitis	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Gastrointestinal disorders Diarrhoea	46.2% 12/26 • From date of first dose to date of last dose of study therapy plus 90 days	40.0% 10/25 • From date of first dose to date of last dose of study therapy plus 90 days
Gastrointestinal disorders Nausea	11.5% 3/26 • From date of first dose to date of last dose of study therapy plus 90 days	8.0% 2/25 • From date of first dose to date of last dose of study therapy plus 90 days
Gastrointestinal disorders Vomiting	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
General disorders Asthenia	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
General disorders Fatigue	34.6% 9/26 • From date of first dose to date of last dose of study therapy plus 90 days	16.0% 4/25 • From date of first dose to date of last dose of study therapy plus 90 days
General disorders Mucosal inflammation	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
General disorders Pain	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	4.0% 1/25 • From date of first dose to date of last dose of study therapy plus 90 days
General disorders Pyrexia	23.1% 6/26 • From date of first dose to date of last dose of study therapy plus 90 days	12.0% 3/25 • From date of first dose to date of last dose of study therapy plus 90 days
Infections and infestations Conjunctivitis	0.00% 0/26 • From date of first dose to date of last dose of study therapy plus 90 days	8.0% 2/25 • From date of first dose to date of last dose of study therapy plus 90 days
Infections and infestations Systemic infection	0.00% 0/26 • From date of first dose to date of last dose of study therapy plus 90 days	8.0% 2/25 • From date of first dose to date of last dose of study therapy plus 90 days
Investigations Weight decreased	11.5% 3/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Metabolism and nutrition disorders Decreased appetite	15.4% 4/26 • From date of first dose to date of last dose of study therapy plus 90 days	4.0% 1/25 • From date of first dose to date of last dose of study therapy plus 90 days
Metabolism and nutrition disorders Dehydration	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	4.0% 1/25 • From date of first dose to date of last dose of study therapy plus 90 days
Metabolism and nutrition disorders Hypokalaemia	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Musculoskeletal and connective tissue disorders Arthralgia	11.5% 3/26 • From date of first dose to date of last dose of study therapy plus 90 days	12.0% 3/25 • From date of first dose to date of last dose of study therapy plus 90 days
Musculoskeletal and connective tissue disorders Back pain	3.8% 1/26 • From date of first dose to date of last dose of study therapy plus 90 days	12.0% 3/25 • From date of first dose to date of last dose of study therapy plus 90 days
Musculoskeletal and connective tissue disorders Pain in extremity	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	8.0% 2/25 • From date of first dose to date of last dose of study therapy plus 90 days
Nervous system disorders Headache	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Psychiatric disorders Insomnia	11.5% 3/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Renal and urinary disorders Haematuria	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Renal and urinary disorders Nocturia	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Reproductive system and breast disorders Pelvic pain	0.00% 0/26 • From date of first dose to date of last dose of study therapy plus 90 days	8.0% 2/25 • From date of first dose to date of last dose of study therapy plus 90 days
Respiratory, thoracic and mediastinal disorders Cough	3.8% 1/26 • From date of first dose to date of last dose of study therapy plus 90 days	8.0% 2/25 • From date of first dose to date of last dose of study therapy plus 90 days
Skin and subcutaneous tissue disorders Eczema	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	0.00% 0/25 • From date of first dose to date of last dose of study therapy plus 90 days
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/26 • From date of first dose to date of last dose of study therapy plus 90 days	8.0% 2/25 • From date of first dose to date of last dose of study therapy plus 90 days
Skin and subcutaneous tissue disorders Pruritus	19.2% 5/26 • From date of first dose to date of last dose of study therapy plus 90 days	16.0% 4/25 • From date of first dose to date of last dose of study therapy plus 90 days
Skin and subcutaneous tissue disorders Rash	34.6% 9/26 • From date of first dose to date of last dose of study therapy plus 90 days	20.0% 5/25 • From date of first dose to date of last dose of study therapy plus 90 days
Skin and subcutaneous tissue disorders Rash maculo-papular	7.7% 2/26 • From date of first dose to date of last dose of study therapy plus 90 days	4.0% 1/25 • From date of first dose to date of last dose of study therapy plus 90 days
Skin and subcutaneous tissue disorders Skin lesion	3.8% 1/26 • From date of first dose to date of last dose of study therapy plus 90 days	8.0% 2/25 • From date of first dose to date of last dose of study therapy plus 90 days
Skin and subcutaneous tissue disorders Urticaria	0.00% 0/26 • From date of first dose to date of last dose of study therapy plus 90 days	8.0% 2/25 • From date of first dose to date of last dose of study therapy plus 90 days
Vascular disorders Hypertension	3.8% 1/26 • From date of first dose to date of last dose of study therapy plus 90 days	16.0% 4/25 • From date of first dose to date of last dose of study therapy plus 90 days